CN117886677A - 一种烯丙基三氟乙基醚类化合物的合成方法 - Google Patents
一种烯丙基三氟乙基醚类化合物的合成方法 Download PDFInfo
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- -1 allyl trifluoroethyl ether compound Chemical class 0.000 title claims abstract description 25
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 16
- FASUFOTUSHAIHG-UHFFFAOYSA-N 3-methoxyprop-1-ene Chemical compound COCC=C FASUFOTUSHAIHG-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 239000000654 additive Substances 0.000 claims abstract description 9
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000000996 additive effect Effects 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 230000035484 reaction time Effects 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003208 petroleum Substances 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- 239000011968 lewis acid catalyst Substances 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 239000011698 potassium fluoride Substances 0.000 claims description 5
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 239000004280 Sodium formate Substances 0.000 claims description 2
- FKOASGGZYSYPBI-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)alumanyl trifluoromethanesulfonate Chemical compound [Al+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F FKOASGGZYSYPBI-UHFFFAOYSA-K 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- PDPJQWYGJJBYLF-UHFFFAOYSA-J hafnium tetrachloride Chemical compound Cl[Hf](Cl)(Cl)Cl PDPJQWYGJJBYLF-UHFFFAOYSA-J 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 2
- 235000013024 sodium fluoride Nutrition 0.000 claims description 2
- 239000011775 sodium fluoride Substances 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 229910001495 sodium tetrafluoroborate Inorganic materials 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 10
- 125000000746 allylic group Chemical group 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical class COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002841 Lewis acid Substances 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 4
- 150000007517 lewis acids Chemical class 0.000 abstract description 4
- 230000033228 biological regulation Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- FEQIPECZADYPJN-CMDGGOBGSA-N [(e)-3-methoxybut-1-enyl]benzene Chemical compound COC(C)\C=C\C1=CC=CC=C1 FEQIPECZADYPJN-CMDGGOBGSA-N 0.000 description 15
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical group BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- BVOLFRMACPTNGV-UHFFFAOYSA-N 1,1,1-trifluoro-2-(2,2,2-trifluoroethoxyperoxy)ethane Chemical compound FC(F)(F)COOOCC(F)(F)F BVOLFRMACPTNGV-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XOURNDFHPYLQDJ-VMPITWQZSA-N [(e)-3-methoxyprop-1-enyl]benzene Chemical compound COC\C=C\C1=CC=CC=C1 XOURNDFHPYLQDJ-VMPITWQZSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000007046 ethoxylation reaction Methods 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 150000005217 methyl ethers Chemical class 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 2
- WNZVSKNJDKQLPA-RMKNXTFCSA-N 1-[(E)-3-methoxybut-1-enyl]-4-methylbenzene Chemical group COC(C)\C=C\c1ccc(C)cc1 WNZVSKNJDKQLPA-RMKNXTFCSA-N 0.000 description 1
- KEBGTAOBADXKPU-ONEGZZNKSA-N 1-chloro-4-[(E)-3-methoxybut-1-enyl]benzene Chemical group COC(C)\C=C\c1ccc(Cl)cc1 KEBGTAOBADXKPU-ONEGZZNKSA-N 0.000 description 1
- UHKKIAPMWVMLSC-SNAWJCMRSA-N 1-methoxy-4-[(E)-3-methoxybut-1-enyl]benzene Chemical group COC(C)\C=C\C1=CC=C(OC)C=C1 UHKKIAPMWVMLSC-SNAWJCMRSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- DQBRFHQAFIYBMG-MDZDMXLPSA-N COC(/C=C/C1=CC=CC=C1)CC Chemical compound COC(/C=C/C1=CC=CC=C1)CC DQBRFHQAFIYBMG-MDZDMXLPSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 1
- YKBWTDGPVYTMKD-MDZDMXLPSA-N [(E)-3-methoxy-3-methylbut-1-enyl]benzene Chemical compound COC(C)(C)\C=C\c1ccccc1 YKBWTDGPVYTMKD-MDZDMXLPSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960004181 riluzole Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/14—Preparation of ethers by exchange of organic parts on the ether-oxygen for other organic parts, e.g. by trans-etherification
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0215—Sulfur-containing compounds
- B01J31/0225—Sulfur-containing compounds comprising sulfonic acid groups or the corresponding salts
- B01J31/0227—Sulfur-containing compounds comprising sulfonic acid groups or the corresponding salts being perfluorinated, i.e. comprising at least one perfluorinated moiety as substructure in case of polyfunctional compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/36—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/40—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation
- C07C41/42—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation by distillation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
- B01J2231/4288—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using O nucleophiles, e.g. alcohols, carboxylates, esters
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Abstract
本发明公开了一种烯丙基三氟乙基醚类化合物的合成方法,以烯丙基甲基醚为原料,在三氟乙醇作溶剂,Lewis酸作催化剂,添加剂及碱的存在下,通过对反应温度的调控实现烯丙位不同种类C上甲基醚的选择性亲核取代,高选择性地得到烯丙基三氟乙基醚类化合物。本发明具有高效、反应条件温和、操作方便、反应时间短、副产物少等优点,并且适合于大规模生产。
Description
技术领域
本发明涉及一种烯丙基三氟乙基醚类化合物的合成方法,通过对烯丙位不同种类C上甲基醚的选择性亲核取代来实现烯丙基三氟乙基醚类化合物的合成,属于有机合成领域。
背景技术
含有醚键的生物活性分子广泛应用于医药、农药等领域。将这些药物分子中的醚键直接进行合成转化,实现对其结构的后期修饰具有重要的药理学意义[1]。氟烷基醚是药物和农药化学发现领域中有价值的结构单元[2,3],与非氟化类似物相比,多氟烷氧基的引入导致了亲脂性[4,5]和代谢稳定性[6,7]的提高。例如,用于治疗肌萎缩侧索硬化症的药物利鲁唑的亲脂性(logD=3.34)高于其非氟化类似物(logD=1.94);六氟异丙氧基类似物甚至更亲脂(logD=3.85)[8]。因此,如何通过合理的方式将药物分子中的醚键选择性地转化为氟烷基醚具有重要意义。
在传统的有机合成路径中,甲基醚的氟烷基醚化通常需要多个合成步骤:首先,通过脱保护反应将醚键转化为醇,再将醇羟基转化为其他活性官能团,如-Br、-Cl等,再在烯丙基溴等易离去官能团的基础上进行亲核多氟烷基取代反应。这种反应过程不仅需要耗费时间和资源,还容易导致产物的低收率和副反应的发生。因此人们更多将目光转移到了醚的直接亲核取代反应。其有如下几个优点:1)缩短合成过程,节约反应时间;2)提高产物收率;3)避免副反应发生,提高反应纯度。综上所述,发展一种对甲基醚进行直接多氟烷基亲核取代的反应具有重要的应用价值。
三氟乙氧基醚合成的直接方法是对烯丙基溴、氯进行亲核取代[9,10]。但该方法仅能对烯丙基伯碳以及仲碳上的溴、氯进行亲核取代,范围有限。如何使用一种良好的方法进行烯丙位不同种类C上的三氟乙氧基化仍然是一个问题。为了解决这个问题,我们在Lewis酸的催化下,通过对反应温度的调控实现了对烯丙位不同种类C上的氢键介导甲基醚的选择性直接三氟乙氧基化反应。该反应具有底物范围广,原料易得,副产物少,反应步骤短等特点,为三氟乙氧基醚的合成提供了一种新的思路。
参考文献:
[1]Schelhaas M.,Waldmann H.Protecting Group Strategies in OrganicSynthesis[J].Angewandte Chemie International Edition in English,2003,35(18):2056-83.
[2]Johnson B.M.,Shu Y.Z.,Zhuo X.,et al.Metabolic and PharmaceuticalAspects ofFluorinated Compounds[J].Journal ofMedicinal Chemistry,2020,63(12):6315-86.
[3]Fre′de′ric L.,Peter J.,Manfred S..α-Fluorinated Ethers,Thioethers,andAmines:Anomerically Biased Species[J].Chemical Review.2005,105,827-856
[4]Corwin H.,Albert L.,Stefan H.U.,et al.“Aromatic”SubstituentConstants for Structure-Activity Correlations[J].Journal ofMedicinalChemistry.1973.16(11)
[5]Corwin H.,Albert L..,and Tafta R.W..Survey of Hammett SubstituentConstants and Resonance and Field Parameters[J].Chemical Review.1991,91,165-195.
[6]O'hagan D..Understanding organofluorine chemistry.An introductionto the C–F bond[J].Chemcal Society Reviews,2008,37(2):308-19.
[7]Wang C.,Chen Z.,Wu W,et al.How the Generalized Anomeric EffectInfluences the Conformational Preference[J].Chemistry–A European Journal,2012,19(4):1436-44.
[8]Su J.,Chen K.,Kang Q.K.,et al.Catalytic SNArHexafluoroisopropoxylation of Aryl Chlorides and Bromides[J].AngewandteChemie International Edition,2023,62(24):
[9]Audouard C,.Garayt M.R.,Kérourédan E.,et al.A direct and rapidroute toα,α-difluoroacylsilanes from trifluoroethanol[J].Journal of FluorineChemistry,2005,126(4):609-21.
[10]Christophe A.,John F.,Hongli Y.,et al.A Potentially Divergent andRapid Route to Analogues ofDeoxycyclitols,Pentopyranoses,6-Deoxyhexoses,andHexoses[J].Organic Letters,2004,6(23):4269-4272.
发明内容
本发明针对醚交换反应具有反应周期长、收率低、副反应多的缺点,以及通过对烯丙基溴的三氟乙氧基化具有反应底物有限的缺点,提供了一种烯丙基三氟乙基醚类化合物的合成方法。本发明方法通过反应温度的调控能够实现烯丙位不同种类C上甲基醚的三氟乙氧基选择性亲核取代反应,该方法具有原料易得、工艺简单、条件温和、产率高、底物范围广、副产物少等优点。
本发明烯丙基三氟乙基醚类化合物的合成方法,以烯丙基甲基醚为原料,以三氟乙醇作为溶剂,在Lewis酸催化剂、添加剂和碱的存在下进行反应,分离提纯后得到烯丙基三氟乙基醚类化合物。
具体是将烯丙基甲基醚溶于溶剂中,在Lewis酸催化剂、添加剂与碱存在下在Shelenk反应管中进行反应,反应结束后分离提纯得到目标产物。
所述烯丙基甲基醚的结构式为:
其中:R1为苯基或含不同取代基的苯基,R2为CH3或H等基团,R3为CH3或H等官能团。
所述Lewis酸催化剂选自三氟甲磺酸锌、三氟甲磺酸钪、三氟甲磺酸铝、三氟甲磺酸、四氯化铪、双三氟甲烷磺酰亚胺中的任意一种,催化剂的添加量为5mol%-50mol%,以烯丙基甲基醚计。
所述碱为氟化钾、甲酸钠、氟化钠中的至少一种,添加量为1-7倍当量,以烯丙基甲基醚计。
所述添加剂为六氟锑酸钠、四氟硼酸钠、六氟磷酸钠中的至少一种,添加剂的添加量为1-7倍当量,以烯丙基甲基醚计。
所述溶剂为三氟乙醇。
本发明合成方法的反应温度为-10℃至100℃,其中伯碳上甲氧基的亲核取代优选在90℃下反应,仲碳上甲氧基的亲核取代优选在70℃下反应,叔碳上甲氧基的亲核取代优选在0℃下反应。反应时间为4-48h,优选为12h。
所述分离提纯是向反应液中加入水,用乙酸乙酯萃取,无水硫酸钠干燥,最后利用旋蒸除去溶剂,通过柱层析分离纯化,柱层析分离纯化时的洗脱液为石油醚:乙酸乙酯=50:1,v/v。
本发明反应路线示意如下:
本发明的有益效果体现在:
1、本发明的合成方法为Lewis酸催化烯丙基甲基醚的三氟乙氧基亲核取代反应,具有反应原料简单易得,工艺简单,条件温和等特点。
2、本发明的合成方法底物适用性广,产率高,副产物少,能兼容多种官能团,适用于芳环上含有多种取代基的烯丙基甲基醚。
附图说明
图1反应产物2h的气相-质谱联用图。
图2反应原料1h的气相-质谱联用图。
图3是反应产物2i的气相-质谱联用图。
图4是反应原料1i的气相-质谱联用图。
具体实施方式
通过单因素条件实验,确认反应过程中碱、Lewis酸、三氟乙醇的存在是必须的。
无添加剂会使得反应收率降低。
在温度的改变(相比于最佳反应条件)会使得反应收率降低。
反应时间的缩短会使得反应不完全,延长反应时间不能进一步提高反应收率。
反应溶剂改变会使得反应不能发生。
条件筛选过程以(E)-(3-甲氧基丁-1-烯-1-基)苯(1a)为模型底物进行,具体实施如下:
表1
表1为使用二苯甲酮作为内标,使用内标法在气相色谱仪(GC)上测量反应产率。
为进一步阐述本发明的特征和优点,下面结合具体的实施例对本发明的技术方案进行描述。但下列实施例仅为了进一步说明本发明,而不是限制本发明。
实施例1:
向装有磁力搅拌子的25mL透明Schlenk管中,加入原料(E)-(3-甲氧基丁-1-烯-1-基)苯(1a)(0.2mmol)、三氟甲磺酸锌催化剂(0.04mmol,20mol%)、六氟锑酸钠(0.4mmol,2eq),KF(0.4mmol,2eq),加入2.0mL三氟乙醇。将反应管固定于70℃的油浴锅中,反应12h后,用水和乙酸乙酯萃取,合并有机相,经无水硫酸钠干燥,然后真空浓缩,产物通过硅胶柱色谱纯化(石油醚:乙酸乙酯=50:1,V/V)得淡黄色液体(2a)(33mg,72%)。该化合物的核磁数据为:1H NMR(600MHz,Chloroform-d)δ7.40(d,J=7.0Hz,2H),7.34(t,2H),7.28(d,1H),6.57(d,J=15.9Hz,1H),6.07(dd,J=15.9,7.9Hz,1H),4.17(p,1H),3.90–3.72(m,2H),1.40(d,3H).13C NMR(101MHz,Chloroform-d)δ136.12,133.02,129.71,128.81,128.27,126.73,124.34(q,J=280Hz)78.58,65.46(q,J=34Hz),21.62.19F NMR(564MHz,Chloroform-d)δ-74.13.
实施例2:
用(E)-1-(3-甲氧基丁-1-烯-1-基)-4-甲基苯(1b)代替(E)-(3-甲氧基丁-1-烯-1-基)苯(1a),其他同实施例1。产物通过硅胶柱色谱纯化(石油醚:乙酸乙酯=50:1,V/V)得无色油状液体(2b)(33mg,68%)。该化合物的核磁数据为:1HNMR(600MHz,Chloroform-d)δ7.31(s,2H),7.16(s,2H),6.55(d,J=15.9,1H),6.02(dd,J=15.9,8.1Hz,1H),4.16(m,1H),3.86-3.77(m,2H),2.36(s,3H),1.41(d,3H).13C NMR(151MHz,Chloroform-d)δ138.21,133.35,133.00,129.50,128.67,126.65,124.36(q,J=280Hz),78.68,65.40(q,J=34Hz),21.66,21.35.19F NMR(376MHz,Chloroform-d)δ-74.06.
实施例3:
用(E)-1-氟-4-(3-甲氧基丁-1-烯-1-基)苯(1c)代替(E)-(3-甲氧基丁-1-烯-1-基)苯(1a),其他同实施例1。产物通过硅胶柱色谱纯化(石油醚:乙酸乙酯=50:1,V/V)得淡黄色液体(2c)(34mg,69%)。该化合物的核磁数据为:1HNMR(600MHz,Chloroform-d)δ7.40–7.34(m,2H),7.03(m,2H),6.54(d,J=15.9Hz,1H),6.00(dd,J=15.9,7.8Hz,1H),4.22–4.11(m,1H),3.92–3.70(m,2H),1.40(d,3H).13C NMR(151MHz,Chloroform-d)δ162.74(m),132.37(m),131.70,129.44(m),128.32(m),124.35(q,J=280Hz),115.73(m),78.48,65.54(q,J=34Hz),21.53.19FNMR(564MHz,Chloroform-d)δ-74.14(s,3F),-113.67(s,1F).
实施例4:
用(E)-1-氯-4-(3-甲氧基丁-1-烯-1-基)苯(1d)代替(E)-(3-甲氧基丁-1-烯-1-基)苯(1a),其他同实施例1。产物通过硅胶柱色谱纯化(石油醚:乙酸乙酯=50:1,V/V)得无色油状液体(2d)(39mg,73%)。该化合物的核磁数据为:1HNMR(600MHz,Chloroform-d)δ7.36–7.28(m,4H),6.52(d,J=15.9Hz,1H),6.06(dd,J=16.0,7.8Hz,1H),4.17(m,1H),3.90–3.72(m,2H),1.40(d,3H).13C NMR(151MHz,Chloroform-d)δ134.67,133.88,131.56,130.45,128.96,127.94,124.28(q,J=280Hz),78.39,65.58(q,J=34Hz),21.49.19F NMR(564MHz,Chloroform-d)δ-74.12.
实施例5:
用(E)-1-溴-4-(3-甲氧基丁-1-烯-1-基)苯(1e)代替(E)-(3-甲氧基丁-1-烯-1-基)苯(1a),其他同实施例1。产物通过硅胶柱色谱纯化(石油醚:乙酸乙酯=50:1,V/V)得无色油状液体(2e)(49mg,80%)。该化合物的核磁数据为:1H NMR(600MHz,Chloroform-d)δ7.45(m,2H),7.26(m,2H),6.50(d,J=15.9Hz,1H),6.07(dd,J=16.0,7.8Hz,1H),4.16(m,1H),3.80(m,2H),1.39(d,3H).13C NMR(151MHz,Chloroform-d)δ135.10,131.89,131.57,130.58,128.24,124.27(q,J=280Hz),122.02,78.36,65.58(q,J=34Hz),21.45.19F NMR(564MHz,Chloroform-d)δ-74.10.
实施例6:
用(E)-1-甲氧基-4-(3-甲氧基丁-1-烯-1-基)苯(1f)代替(E)-(3-甲氧基丁-1-烯-1-基)苯(1a),其他同实施例1。产物通过硅胶柱色谱纯化(石油醚:乙酸乙酯=50:1,V/V)得无色油状液体(2f)(27mg,52%)。该化合物的核磁数据为:1H NMR(400MHz,Chloroform-d)δ7.34(m,2H),6.88(m,2H),6.50(d,J=15.9Hz,1H),5.92(dd,J=15.9Hz,8.1Hz,1H),4.19–4.09(m,1H),3.82(s,3H),3.90–3.70(m,2H),1.39(d,3H).13C NMR(101MHz,Chloroform-d)δ159.72,132.65,128.84,127.97,124.38(q,J=280Hz),114.18,78.76,65.33(q,J=34Hz),55.45,21.73.19FNMR(564MHz,Chloroform-d)δ-74.09.
实施例7:
用(E)-(3-甲氧基戊-1-烯-1-基)苯(1g)代替(E)-(3-甲氧基丁-1-烯-1-基)苯(1a),其他同实施例1。产物通过硅胶柱色谱纯化(石油醚:乙酸乙酯=50:1,V/V)得淡黄色液体(2f)(35mg,72%)。该化合物的核磁数据为:1H NMR(400MHz,Chloroform-d)δ7.47–7.41(m,2H),7.41–7.34(m,2H),7.34–7.28(m,1H),6.59(d,J=16.0Hz,1H),6.06(dd,J=16.0,8.3Hz,1H),3.97–3.71(m,3H),1.88–1.61(m,2H),1.00(t,3H).13C NMR(151MHz,Chloroform-d)δ136.14,133.01,129.73,128.82,128.27,126.74,124.35(q,J=280Hz),78.57,65.49(q,J=34Hz),
21.62.19F NMR(564MHz,Chloroform-d)δ-74.10.
实施例8:
向装有磁力搅拌子的25mL透明Schlenk管中,加入原料(E)-(3-甲氧基丙-1-烯-1-基)苯(1h)(0.2mmol)、三氟甲磺酸锌催化剂(0.04mmol,20mol%)、六氟锑酸钠(0.4mmol,2eq),KF(0.4mmol,2eq),加入2.0mL三氟乙醇。将反应管固定于90℃的油浴锅中,反应12h后将反应液简单处理后送GC-MS。监测到反应产物2h的生成。
反应产物2hMW=216
反应原料1hMW=148
实施例9:
向装有磁力搅拌子的25mL透明Schlenk管中,加入原料(E)-(3-甲氧基-3-甲基丁-1-烯-1-基)苯苯(1i)(0.2mmol)、三氟甲磺酸锌催化剂(0.04mmol,20mol%)、六氟锑酸钠(0.4mmol,2eq),KF(0.4mmol,2eq),加入2.0mL三氟乙醇。将反应管固定于0℃的低温反应器上,反应12h后将反应液简单处理后送GC-MS。监测到反应产物2i的生成。
反应产物2iMW=244
反应原料1iMW=176
Claims (10)
1.一种烯丙基三氟乙基醚类化合物的合成方法,其特征在于:
以烯丙基甲基醚为原料溶于溶剂中,在Lewis酸催化剂、添加剂和碱的存在下进行反应,分离提纯后得到烯丙基三氟乙基醚类化合物;
所述烯丙基甲基醚的结构式为:
其中:R1为苯基或含不同取代基的苯基,R2为CH3或H基团,R3为CH3或H基团。
2.根据权利要求1所述的合成方法,其特征在于:
所述Lewis酸催化剂选自三氟甲磺酸锌、三氟甲磺酸钪、三氟甲磺酸铝、三氟甲磺酸、四氯化铪、双三氟甲烷磺酰亚胺中的任意一种。
3.根据根据权利要求2所述的合成方法,其特征在于:
所述Lewis酸催化剂的添加量为5mol%-50mol%,以烯丙基甲基醚计。
4.根据根据权利要求1所述的合成方法,其特征在于:
所述碱为氟化钾、甲酸钠、氟化钠中的至少一种。
5.根据根据权利要求4所述的合成方法,其特征在于:
所述碱的添加量为1-7倍当量,以烯丙基甲基醚计。
6.根据根据权利要求1所述的合成方法,其特征在于:
所述添加剂为六氟锑酸钠、四氟硼酸钠、六氟磷酸钠中的至少一种。
7.根据根据权利要求6所述的合成方法,其特征在于:
所述添加剂的添加量为1-7倍当量,以烯丙基甲基醚计。
8.根据根据权利要求1所述的合成方法,其特征在于:
所述溶剂为三氟乙醇。
9.根据根据权利要求1所述的合成方法,其特征在于:
反应温度为-10℃至100℃,反应时间为4-48h。
10.根据根据权利要求1所述的合成方法,其特征在于:
所述分离提纯是向反应液中加入水,用乙酸乙酯萃取,无水硫酸钠干燥,最后利用旋蒸除去溶剂,通过柱层析分离纯化,柱层析分离纯化时的洗脱液为石油醚:乙酸乙酯=50:1,v/v。
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